The invention disclosed herein deals in one embodiment with cellular hydrogels and methods for their preparation. The hydrogels of this invention can be colored, rendered radio opaque, or can be complexed, for example, with iodine and/or other germicides to yield useful materials.
The hydrogels can be formed into essentially any shape, size, or surface texture, and can have a wide range of desired degrees of porosity, that is, have any pore size, or pore geometry, or any pore size/geometry distribution.
The methods for preparing the hydrogels require dissolution of the precursor polymers in either single or mixed solvents capable of dissolving the polymer. The polymer solution is then loaded with a material (described infra) that creates the continuous polymer network structure with the embedded material. The mixture is then subjected to conditions that cause crystallization, gellation, or coagulation, or a mixture of crystallization, gellation, or coagulation, of the polymer through formation of physical sites. Thereafter, the material is removed to provide a cellular hydrogel.
The cellular hydrogels can then be subjected to a solvent treatment and/or a heat treatment to modify and further tailor the physical properties.
In an alternative method, the polymer is first dissolved in a solvent for the polyvinyl alcohol (PVA), or a mixture of solvents for the PVA, and a stable froth is prepared through the use of surface active agents or a mixture of surface active agents. The froth is then subjected to conditions that cause crystallization, gellation, coagulation or a mixture of crystallization, gellation, or coagulation, of the polymer through the formation of physical sites. The hydrogels formed in this manner can then be subjected to a solvent treatment or heat treatment to modify and further tailor the physical properties of the hydrogels.
The published literature is abundant with references to various types of cellular materials made from polymers such as polyurethanes, polystyrenes, polyolefins, polyvinylchloride, epoxies, urea-form aldehyde, latices, silicones, fluoropolymers, and a number of other polymers. Numerous methods for the preparation and controlling the physical properties of cellular materials have been disclosed in the literature.
Manufacturing processes for making cellular polymers are well known to those skilled in the art with regard to bulk (solid) polymers. Typically, cellular polymers are made either by mechanically entrapping gas bubble in a polymer matrix or by incorporating removable, materials. Commonly, gas bubbles of nitrogen and carbon dioxide are mechanically entrapped either under normal atmospheric pressure or generated by sudden expansion of gas dissolved in the polymer matrix upon decrease of the pressure. Cellular structures can also be created by entrapping gas generated through a chemical reaction of an expansion agent or blowing agent. For instance, one can entrap carbon dioxide released during the chemical reaction of sodium bicarbonate and an acid. Usually, the chemical foaming methods are preferred over mechanical, that is, physical foaming methods. This is because, when physical foaming methods are used, it is, for instance, difficult to ensure homogeneous distribution of entrapped gas in the polymer matrix, control reduction of gas pressure, and control the diffusion rate of a gas out of the polymer matrix.
Those methods that have been reported in the literature for the preparation of PVA hydrogels can be divided into methods that rely on covalent cross-linking in one approach, and those methods that involve physical cross-linking.
The first method, covalent cross-linking, also known as chemical cross-linking, includes the use of multi-functional reactive molecules, that is, cross-linkers, such as aldehydes, maleic acid, dimethylurea, diisocyanates, boric acid and also includes ionizing radiation, ultra-violet, or any other agent capable of creating covalent cross-links between molecules. This method has been used to prepare bulk (non-porous) and cellular (porous) hydrogels.
The second, or alternative method, also known as physical or reversible cross-linking, includes cross-linking through crystallites, hydrogen bonding and complexing. Physical cross-linking through formation of crystallites in situ is the most desirable and can be accomplished by single freezing and then de-freezing; repeated freezing and de-freezing; partial or complete freeze-drying; controlled low temperature crystallization and the like.
A review of the prior art shows that physical cross-linking methods have been used only to prepare bulk hydrogels. No references related to the preparation of cellular hydrogels by physical cross-linking were found. The first of these references is U.S. Pat. No. 2,609,347, which issued to Wilson in 1952. This reference teaches the preparation of covalently cross-linked porous hydrogels by cross-linking the polymers with formaldehyde at temperatures between 20xc2x0 C. and 60xc2x0 C. in the presence of acid catalysts, such as sulfuric acid. The method is a frothing method, in that, porous structures are created by entrapping gas bubbles in the polymer solution in the presence of a wetting agent which stabilizes bubbles and helps to disperse the bubbles uniformly throughout. This patent also discloses the possibility of using cross-linked polymer hydrogels in a number of applications including the use as implants in the human body.
Since the publication of that patent, a number of methods, based on a covalent cross-linking of PVA as disclosed in the ""347 patents have been reported for making cellular materials. In all cases of the prior art, the first step in the preparation of cellular hydrogels is dissolution of the polymer or its copolymers in an appropriate solvent, typically water. The next step is entrapment of air bubbles in the polymer solution in the presence of a surfactant and finally, cross-linking the polymer by treating it with di- or multi-functional cross-linkers.
All cross-linking agents used in the prior art render the sponges intractable and thus making them insoluble in any solvent due to formation of covalent bonds between molecules. Typically, cross-linking agents for the PVA were selected from the aldehyde family, such as formaldehyde, glyoxal, glutaraldehyde, terephthaldehyde and hexamethylenealdehyde that leads to formation of highly acetalized cellular PVA networks. PVA can also be cross-linked with unsaturated nitrites, di-diisocyanates, trimethylolmelamine, epichlorohydrin, polyacrylic acid, dimethylolurea, maleic anhydride, boric acid, sodium tetraboratedecahydrate (Borax) or by exposure to high-energy radiation.
Covalently cross-linked PVA sponges and bulk PVA hydrogels have a relatively long history of use in a wide variety of applications. Covalently cross-linked PVA sponges have already established themselves as very useful materials in numerous applications such as in packaging, thermal and acoustic insulation, construction, furniture, transportation, aerospace, food industry, household, textile, medical cosmetics and a number of other areas. For example, covalently cross-linked cellular PVA are used commercially as filters for water, air filters in intakes of compressors, engines, and air conditioners, oil filters, and the like. Large numbers of uses of PVA sponges are also based on their ability to readily absorb and hold water such as household washing sponges, absorbent cloths, industrial dehydrating rollers, paint rollers, acoustic filters, and the like.
The use of PVA sponges and PVA hydrogels in the medical field is especially important because of unique physico-chemical properties of PVA hydrogels. In spite of some incompatibility concerns and physical property limitations, acetalized PVA sponges have readily found significant use in medical fields such as, in cardio-vascular applications. Some of the important unique properties of acetalized PVA sponges are, for instance, being impervious to attack by body fluids such as, for example, blood, urine and other secretions; being non-sticking and non-adherent to tissue and having reasonably good biocompatibility.
The following patents disclose the use of PVA. For example, foams in cosmetics can be found in Japanese kokai 62/072,732 published in April of 1987 to Csawas; thermal insulation in U.S. Pat. No. 4,644,014 which issued to Thomson in February of 1987; pharmaceuticals in Japanese kokoku 57/006,403 which published in February of 1982; medical applications in German Patent 2,523,287 and finally, Japanese Patent 55/071,532 discloses water absorption.
Patents such as U.S. Pat. No. 2,609,347, U.S. Pat. No. 2,668,153, and U.S. Pat. No. 2, 825,747, teach a frothing process for the preparation of PVA sponges from concentrated, viscous aqueous solutions of PVA by cross-linking the PVA with formaldehyde. The solutions are typically vigorously mixed to incorporate gas bubbles into the PVA solutions that are then acidified at or above 60xc2x0 C. to induce covalent cross-linking. This type of PVA sponge is commercially available from a number of sources, but the best-known brand name is Ivalon(copyright) from Unipoint Industries, High Point, N.C.
U.S. Pat. No. 4,098,728 teaches a frothing process to make uniformly expandable hydrophilic sponge by reacting PVA with formaldehyde in the presence of an inorganic acid and non-toxic wetting agent at temperatures of 30xc2x0 C. to 60xc2x0 C. After the PVA has been cross-linked, substantially all of the elutable acid, wetting agent, and formaldehyde are extracted from the sponge. This sponge is suitable for medical use and is characterized by instantaneous wicking and high liquid holding capacity. The rate of wicking and liquid holding capacity of these sponges is controlled by temperature and processing conditions during the formation and curing of reaction product in aqueous medium. This patent also discloses a method of making PVA sponge x-ray opaque by incorporating and homogeneously distributing throughout the PVA sponge, an encapsulated radio opaque substance.
Further, U.S. Pat. No. 4,430,447 discloses a frothing method for manufacturing molded articles from open pore PVA foam that has been covalently cross-linked with aliphatic aldehyde in the presence of wetting agent and acid. This invention also teaches preparation of open pore foams from a mixture of an aqueous PVA solution and an aqueous dispersion of a vinyl acetate/ethylene copolymer by frothing and cross-linking corresponding polymer networks with aliphatic aldehyde in the presence of an acid. Still further, U.S. Pat. Nos. 5,554,658 and 5,554,659 disclose a frothing process for making injection molded porous PVA sponge by reacting PVA with formaldehyde in the presence of a mineral acid, thickening agents and non-toxic wetting agents at temperatures of 50xc2x0 C. to 95xc2x0 C. Preferred degree of acetalization is at least 50% and preferably over 70%. It also teaches a method for making an outer skin on articles of molded PVA sponge.
Going still further, U.S. Pat. No. 5,843,060 discloses a frothing process for preparation of acetalized PVA foam that is useful for making non-adherent nasal, sinus and otic packings. Frothing aqueous solutions of PVA in the presence of wetting agents and gas produces acetalized PVA foam. Frothed PVA is then cross-linked with an organic compound containing two hydroxyl reactive groups in the presence of an inorganic acid catalyst.
Finally, U.S. Pat. No. 5,147,344 discloses a frothing process for preparation of PVA foams based on gelatin and water. The foam is stabilized by covalently cross-linking polymers with multi-function cross-linking agents selected from the group comprising at least trivalent metals or semi-metal or organic or inorganic acids or salts thereof. The foam optionally may contain plasticizers and/or auxiliary agents and/or additives.
With regard to pore-forming methods, one can note from U.S Pat. No. 4,083,906, that the preparation of PVA sponges by using polyethylene glycol and polyacrylamide having various molecular weights, as removable pore-forming substances is disclosed. PVA solution is first mixed with the pore-forming substance and then the PVA is cross-linked with aldehydes in the presence of acid. The pore-forming substance is practically inert to aldehyde reactions. Acid, and water soluble substances are washed out with water.
Another method is taught in U.S. Pat. No. 4,279,752, in which the use of fine silica particles as pore-forming substances in the manufacture of PVA sponges provides sponges with very fine pores. The coagulation of PVA having degrees of hydrolysis as low as 85% is carried out in the presence of an acid, base, or salt. Coagulation-causing substances and the solids are substantially extracted from coagulated PVA. Silica is extracted by alkali solutions such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. This patent is limited to making PVA membranes with pore sizes from 50 angstroms to 10 xcexcm.
U.S. Pat. No. 4,073,733 discloses the preparation of uniform, porous PVA membranes having micro pores made by a process comprising dissolving a polyoxyalkylene glycol into PVA aqueous solutions, coagulating the resulting solutions to form a membrane and removing the polyoxyalkylene glycol by extraction. The membranes obtained according to this invention have average pore sizes of 0.002 to 2 microns and show excellent performance in the separation of small particles.
In other methods of preparation there is shown in U.S. Pat. No. 5,494,940, U.S. Pat. No. 5,502,082, and U.S. Pat. No. 5,541,234, the preparation of highly porous PVA hydrogel bodies having high surface area and open cell structures and articles made from those polymers. The porosity in the hydrogels is created by a process that exposes a PVA solution to a gelling solvent and then gradually replaces that solvent with a cross-linking solvent using a concentration gradient solvent-exchange process. This process leads to coagulation of the PVA in the form of porous freestanding gels that afterward are covalently cross-linked with multi-functional cross-linking agents, preferably by diisocyanates.
U.S. Pat. No. 5,573,994 teaches a method for preparation of super absorbent, microporous foams comprising a cross-linked polymer having interconnected cells distributed throughout its body. The method requires that a cross-linkable polymer be first dissolved to form a stable solution. This stable solution is induced to phase separate into polymer rich and polymer depleted phases and then the polymer is cross-linked to microporous structures. This foam is capable of having exceptionally rapid sorption rates.
U.S. Pat. No. 5,200,786 teaches a method of manufacturing hot water soluble towels, sponges and gauzes based on a PVA fiber structure. PVA fibers are soluble in aqueous solutions above approximately 93xc2x0 C. The articles manufactured according to this invention are based on fabrics made from non-woven PVA fibers that have been either hydro entangled, thermo bonded or chemically bonded together. The articles of this invention are not typical sponges or foams but bonded or entangled fibrous bodies that perform functions typically associated with sponges and foams.
U.S. Pat. No. 4,663,358 that issued to Ikada deals with physically cross-linked PVA hydrogels.
U.S. Pat. No 4,098,728 discloses a method for incorporating into an acetalized PVA sponge, a radio opaque material such as barium sulfate at 6 to 12 weight percent.
U.S. Pat. No. 5,071,648 teaches a composition comprising complexes between acetalized PVA and iodine, useful in antimicrobial applications such as in controlling infection by releasing a desired amount of iodine as an antimicrobial agent. The articles made using this complex are useful in a number of applications, especially in wound dressings.
In other antimicrobial applications, U.S. Pat. Nos. 5,774,150 and 5,928,665 teach methods of preparation of an antimicrobial material by creating a complex between iodine and acetalized foam. Acetalized PVA foam can also be impregnated with a polyol from water solution to create soft foam that will not dry in air nor will it become rigid. The impregnation with polyol has another advantage, that is, its presence accelerates formation of iodates and iodine oxide.
Finally, U.S. Pat. No. 5,071,648 teaches a process for making an antimicrobial absorbent material based on acetalized PVA sponge comprising binding disinfectant dyes to PVA matrices. The articles made from it are desirable for wound dressings or for uses in body orifices for preventing or abating infections.
In his book, Polyvinyl Alcohol Fibers, Sakurada (1985), in Chapter 9, reviews different heat treatment procedures for PVA fibers. For example, he describes typical dry heat treatment of PVA fibers that is carried out in air at 200xc2x0 C. to 230xc2x0 C. for 10 to 30 seconds. Wet heat treatment of PVA fibers is carried out in an autoclave containing aqueous solutions of inorganic salts such as for example, ammonium sulfate or sodium sulfate, at around 130xc2x0 C. Both of these processes are believed to lead to the increase of the degree of crystallinity and hydrogen bonding of PVA. Furthermore, in Chapters 8 and 11 of the same book, coagulation procedures for spinning PVA fibers using aqueous solutions of sodium sulfate and alkali are also reviewed. All of these procedures are of importance for making and improving properties of cellular PVA hydrogels when using the methods of the present invention.
Thus, the prior art relating to making cellular PVA hydrogels teaches the use of chemical means, that is, the creation of covalent bonds between PVA molecules to permanently stabilize the cellular PVA structure. Most often used, as cross-linking agents, are those from the aldehyde family, and high energy radiation such as electron beam or gamma-ray, all of which create intractable and thus, covalently cross-linked PVA hydrogels insoluble in any solvent.
Acetalized PVA sponges made by aldehyde, have typically 25 to 55%, and often over 70% of alcohol functional groups acetalized. Such a high degree of acetalization of PVA is necessary for covalently cross-linked PVA hydrogels to have reasonable mechanical properties. However, a high s degree of acetalization of PVA leads to a loss of too many hydroxyl groups that may significantly change biocompatibility characteristics. High degrees of acetalization of PVA sponges may also impose severe limitations for a number of uses because of some undesirable physical properties of such PVA sponges. For examples, high degrees of cross-linking of PVA sponges dramatically limits the polymer chain mobility making highly cross-linked PVA hydrogels hard, rigid, abrasive and sometimes too brittle, especially when dry, or low water content hydrogels are obtained. The higher the extent of acetalization of PVA, the harder, more abrasive, more rigid and more hydrophobic, PVA sponges become.
The inventor herein has not found any reference for preparing physically cross-linked cellular PVA hydrogels by using either extractable, pore-forming materials or a frothing method. The invention herein teaches the methods, processes and the like for making and modifying properties of cellular PVA hydrogels by using solvent and/or heat treatment, tailoring properties in wide ranges by selecting desirable processing parameters and/or molecular parameters of components and also manufacturing articles from physically cross-linked cellular PVA hydrogels. In this invention, wide ranges of pore-forming materials or surface active agents can be used to produce cellular PVA hydrogels having remarkable tensile properties and exceptionally wide ranges of physical properties.
One objective of this invention is to provide for the preparation of cellular PVA hydrogels by using various methods to induce physical cross-linking of the PVA molecules free of any additive or any dangling or unreacted functional groups. Another object of this invention is to provide for the preparation of cellular PVA hydrogels by using a wide range of hydrophilic, hydrophobic and biodegradable pore-forming materials which can be removed from the physically cross-linked PVA network. Yet another objective of this invention is to provide for the preparation of cellular PVA hydrogels by using a frothing method.
Still another objective of this invention is to disclose a process for tailoring the physical properties of cellular PVA hydrogels by selecting proper molecular parameters of all ingredients and processing parameters such as, for example, the extent of loading and efficiency of packing of the pore-forming material, the nature and form of pore-forming materials; the nature of the surface active agents, and the use of solvent treatment and heat treatment procedures to modify the properties of cellular PVA hydrogels.
Yet another objective is to disclose methods to color and/or make such PVA hydrogels radio opaque and finally, there is an objective of disclosing the complexing of iodine and the PVA hydrogels and the binding of other germicidal agents to such PVA matrices in the cellular PVA hydrogels.